Researchers discover mitochondrial OMA1-DELE1-HRI axis as ancient haem sensor and translation regulator
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Researchers have uncovered a molecular pathway inside mitochondria that senses haem levels and adjusts protein synthesis accordingly. The pathway involves the OMA1 protease, the DELE1 protein, and the HRI kinase, and is evolutionarily conserved from humans to bloodless invertebrates. The findings, published in Nature, suggest a primordial sentinel system against haem toxicity.
The Haem-Sensing Mechanism
Haem deficiency triggers the OMA1 protease inside mitochondria to cleave and release DELE1 into the cytosol. Once there, DELE1 binds to HRI and displaces inhibitory haem, activating the kinase to phosphorylate eIF2α and repress global translation. This pathway explains how cells couple haem availability to protein synthesis, a control proposed over 50 years ago but missing its molecular players until now.
Evolutionary Conservation
The OMA1–DELE1–HRI axis functions across human tissues, including erythroid progenitors, and is conserved in organisms that lack blood and haemoglobin, such as Caenorhabditis elegans. The system predates the emergence of haemoglobin-based oxygen transport, indicating a primordial defence against haem-related toxicity that is fundamental to eukaryotic life.
Therapeutic Potential
Pharmacological modulation of this pathway boosts fetal globin expression, a central goal in treating haemoglobinopathies like sickle cell disease and β-thalassaemia. The discovery opens new avenues for therapies that target the mitochondrial sentinel to mitigate anaemia and haem disorders affecting over one-quarter of the world's population.
What's Next
Further preclinical studies are expected to test small molecules that engage the OMA1–DELE1–HRI pathway. It remains unclear how this ancient mechanism coordinates with tissue-specific haem regulation in complex organisms.
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Researchers discover mitochondrial OMA1-DELE1-HRI axis as ancient haem sensor and translation regulator
